Synthesis of a hydrazone β-keto ester by the reaction with a diazo ester

ABSTRACT

The present invention relates to the synthesis of a hydrazone β-keto ester by the reaction of an alkyl diazoester with a hydrazone aldehyde in the presence of a Lewis acid In a preferred embodiment, the hydrazone β-keto ester is then converted into a pyridazinone compound by the reaction with an alkyl acid chloride in the presence of a base, followed by acidification. A process for the production of a hydrazone aldehyde, which comprises contacting a hydrazine and glyoxal, is also described.

The present application claims the benefit of U.S. ProvisionalApplication Ser. Nos. 60/024,963, filed Aug. 30, 1996 and 60/043,455,filed Apr. 10, 1997.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to a process for makingpyridazinone derivatives and a hydrazone aldehyde precursor.

2. Description of Related Art

Certain carboxy substituted 4-oxo-1,4-dihydropyridazines and carboalkoxysubstituted 4-oxo-1,4-dihydropyridazines are known in the art to haveplant gametocidal activity and plant growth regulatory activity. Currentmethods for producing the above compounds typically use expensive rawmaterials and/or result in low yields of product. For example, U.S. Pat.Nos. 4,707,181; 5,026,880; and 4,732,603 disclose preparing the abovecompounds by reacting a 2-phenylhydrazono-3-oxoglutarate with an organicacid chloride in the presence of a Grignard reagent (isopropyl magnesiumchloride). The Grignard reagents are expensive and low yields areobtained. U.S. Pat. Nos. 5,189,163 and 5,010,192 also disclose usingexpensive raw materials, such as methyl-3-oxopentanoate, and result inlow yields.

The present invention provides a more efficient process for makingpyridazinone derivatives which results in higher yields of product anduses lower cost raw materials, hydrazone aldehyde and diazo acetate.

Hydrazone aldehydes are useful as precursors in the production of thecarboxy substituted 4-oxo-1,4-dihydropyridazines and carboalkoxysubstituted 4-oxo-1,4-dihydropyridazines mentioned above. Such hydrazonealdehydes, such as 4-chlorophenylhydrazone aldehyde (ethanedial,mono[(4-chlorophenyl)hydrazone]), have typically been made by batchprocesses, wherein one reactant is added to a reactor containing theother reactant. However, such batch processes lead to a lower payload(2-5%). An increase in the payload above 5% made the reaction slurrydifficult to mix and thus resulted in by-product formation. In addition,the water content of the resulting solution is about 80% in a batchprocess, making the solution difficult to wash and handle, and causingfiltration of the product to be very slow. The high water content alsoleads to very long drying times of the product.

An improved process to produce hydrazone aldehydes having a decreasedwater content would lead to a solution which is easier to handle, anddecreased filtration and drying times of the product.

SUMMARY OF THE INVENTION

The present invention relates to the synthesis of a hydrazone β-ketoester by the reaction of a diazo ester with a hydrazone aldehyde in thepresence of a Lewis acid. In a preferred embodiment, the hydrazoneβ-keto ester is then converted into a pyridazinone compound by thereaction with an alkyl acid chloride in the presence of a base, followedby acidification.

More particularly, the present invention relates to the synthesis of ahydrazone β-keto ester having the general Formula III: ##STR1## byreacting a diazo ester with a hydrazone aldehyde in the presence of aLewis acid.

The hydrazone β-keto ester can then be reacted with an alkyl acidchloride in the presence of a base, followed by acidification to producepyridazinone compounds having the general Formula I: ##STR2## or thegeneral Formula II: ##STR3##

The present invention also relates to a continuous process for theproduction of a hydrazone aldehyde comprising contacting a hydrazine andglyoxal, wherein the hydrazine and the glyoxal are added simultaneouslyto a reactor at a controlled rate, preferably between about 10 mL/minand about 100 mL/min.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention relates generally to a process for makingpyridazinone derivatives and preferably to a process for making acompound of Formula I: ##STR4## wherein R₁ is an alkyl, cycloalkyl, arylor heteroaromatic group; R₂ is an alkyl group; and R₃ is an alkyl orphenyl group. Alkyl groups useful in the processes of the presentinvention include straight-chain, branched-chain or cyclic alkyl groupshaving between about 1 and 12 carbon atoms. Preferably the alkyl groupshave from 1 to about 5 carbon atoms. Aryl in a given case can be phenyland can be substituted with one or more lower alkyl groups and/or one ormore halogen atoms such as Cl, Br or F and/or lower alkoxy group.Heteroaromatic groups include: furanyl, thienyl, pyridyl, etc., and canbe optionally substituted as described in the case of phenyl groups.

In a preferred embodiment, the present invention relates to theproduction of pyridazinone compounds of Formula II: ##STR5## wherein R₁' is an alkyl and/or halo group, R₂ ' is an alkyl group and R₃ ' is analkyl or phenyl group.

The pyridazinone compounds of Formula I and II have plant gametocidalactivity and plant growth regulatory activity. In the process ofproducing the pyridazinone compounds of Formula I and II, a β-keto esteris produced by reacting a hydrazone aldehyde with a diazo ester in thepresence of a Lewis acid. The β-keto ester has the general Formula III:##STR6## wherein R₁ and R₂ are as previously described. β-Keto esterscan also be used in the synthesis of pyrazoles, which are used toprepare drugs, dyes and crop protection agents. The reaction can begenerally described as follows: ##STR7## wherein R₁ and R₂ are aspreviously described.

The reaction of the hydrazone aldehyde and alkyl diazoester to produce aβ-keto ester can be conducted in the presence of a solvent. Solventsuseful in the reaction of hydrazone aldehyde with diazo ester includeorganic solvents such as toluene, cumene, benzene, ethylbenzene, diethylether, dibutyl ether, butyl ethyl ether, chlorobenzene, nitrobenzene,ortho-dichlorobenzene, and chlorinated hydrocarbons such as methylenechloride and dichloroethane.

Alkyl diazoesters used in Reaction I to produce the β-keto ester arecommercially available, such as from Aldrich Chemical Co., or can beproduced as disclosed in U.S. Pat. Nos. 2,490,714; 2,691,649; and2,691,650.

The hydrazone aldehyde can be added as a solid or in a slurry. Lewisacids suitable for use in this reaction have been previously described.For example, see Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989,54, 3258. Lewis acids which are suitable in this reaction include SnCl₂,ZnCl₂, ZrCl₄, AlCl₃, TiCl₄, SnCl₄, ZrCl₄ (THF)₂, zeolites, SnCl₂+triphenylmethyl chloride (TMSCl), and SnCl₂ +TMSCl. Mixtures of Lewisacids can also be used. Preferred Lewis acids are SnCl₂ and SnCl₄, andthe Lewis acid should be present in a catalytic amount, typicallybetween about 5 mol % and 25 mol %. The reaction is generally started ata temperature below room temperature, typically between about 0° C. andabout 25° C., and gradually allowed to warm to room temperature duringthe course of the reaction. The hydrazone aldehyde and diazo ester aretypically added in approximately stoichiometric proportions, althoughratios of hydrazone aldehyde to diazo ester of about 2:1 to about 1:2can also be used.

The β-keto ester is then treated with a base and an alkyl acid halide,followed by acidification, to produce a compound of Formula I as shownbelow: ##STR8## wherein R₁, R₂ and R₃ are as described previously, and Xis a halide, preferably chloro or bromo.

Reaction II of the β-keto ester with an alkyl acid halide and base canalso be conducted in the presence of a solvent as described above. Theβ-keto ester can be purified prior to use in this reaction or can beused directly from Reaction I without purification. Bases useful in thisreaction are generally described below, and a preferred base is Ca(OH)₂.A preferred alkyl acid halide suitable in this reaction is propionylchloride. Reaction II can also be conducted in the presence of anacylation catalyst, such as pyridine or a substituted pyridine,preferably 4-dimethylaminopyridine (DMAP), polymer-supported DMAP, or4-(4-methyl-1,1-piperidinyl)pyridine. Acids useful in the acidificationthat follows are generally any acid known for such acidification, andthe acid is preferably HCl, H₂ SO₄ or H₃ PO₄.

Reaction II is preferably conducted at a temperature between about 0° C.and about 40° C. The acid halide and base are generally added in slightexcess, such that the ratio of acid halide to b-keto ester or the ratioof base to b-keto ester is between about 1:1 to about 3:1. The acylationcatalyst can be used in an amount between about 0 and 15 mol %,preferably between about 8 and 10 mol %.

Bases which can be used in the processes of the present inventioninclude both organic and inorganic bases. Suitable inorganic basesinclude Group I and II metal hydrides, hydroxides and oxides, such assodium hydride, calcium hydroxide, calcium oxide, barium hydroxide,barium oxide, magnesium hydroxide, magnesium oxide and the like.Suitable organic bases include both alkyl and aromatic bases such asalkyl, cycloalkyl and aryl amines, metallic amides and aromatic amines.Suitable alkyl and aryl amines include diethylamine, triethylamine,benzylamine, piperidine, piperazine, pyrrolidine and the like.Alkylamines, such as triethylamines, are preferred. Suitable metallicamides include sodium amide and lithium diisopropyl amide. Suitablearomatic amines (aromatic, nitrogen heterocylic compounds) includeimidazole, methylimidazole, pyrazole, pyridine, pyrimidine, pyridazineand the like, preferably pyridines. Those skilled in the art willappreciate that other bases can be utilized in the process of thepresent invention.

As an initial matter, the hydrazone aldehyde used in Reaction I toproduce the β-keto ester can be made from a hydrazine. For instance, asubstituted hydrazine can be reacted in the presence of a glyoxalsolution to form a hydrazone aldehyde: ##STR9## wherein R₁ is aspreviously described. The hydrazone aldehyde can be made by either abatch or continuous process, preferably by a continuous process. It hasbeen found that when a hydrazine and glyoxal are contacted in acontinuous process, such that the reactants are added simultaneously ata controlled rate near one another in physical proximity, the resultinghydrazone aldehyde composition comprises less than about 50% by weightwater, compared to about 80% by water occasioned in a batch process.Such reduction in water content leads to easier handling of the productand decreased filtration and drying times. Typical flowrates for theaddition of the hydrazine and glyoxal are between about 10 and 100mL/min, preferably between about 10 and 50 mL/min. The ratio of thehydrazine to glyoxal is generally between about 1:1 to 1:1.5, preferablybetween about 1:1 and 1:1.25

The continuous process of Reaction III can be conducted in any type ofcontinuous reactor, preferably a continuous stirred tank reactor (CSTR).The temperature of the hydrazone aldehyde synthesis in the continuousprocess is generally between about 40° C. and 70° C., preferably betweenabout 50° C. and 70° C. When a batch process is used for Reaction III,the temperature is generally at or below room temperature, and onereactant is added to a batch reactor containing the other reactant.Hydrazone aldehydes are also useful as precursors in the production ofcertain carboxy substituted 4-oxo-1,4-dihydropyridazines and carboalkoxysubstituted 4-oxo-1,4-dihydropyridazines, which are known to havegametocidal activity.

A compound of the general Formula I can be converted to the acid andthen the salt form using standard procedures, such as those disclosed inU.S. Pat. No. 5,026,880. For example, the solid free acid can be made bytreatment of the compound of Formula I with NaOH, followed byacidification with HCl: ##STR10## The potassium salt can subsequently bemade by treatment of the free acid with KOH.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLE 1

This example illustrates Reaction III, the production of a hydrazonealdehyde from a hydrazine, in a batch process.

To a mixture of 100.0 g (0.56 mol) of 4-chlorophenylhydrazinehydrochloride in 2000 mL of water was added 167.7 g (1.15 mol) of a 40%glyoxal solution in water along with 500 mL of water. The stirred slurrywas maintained at 15-20° C. for 4 h. The hydrazone was then filtered anddried to yield 94 g (92.5% yield) of yellow solid, m.p. 150-15° C. Theproduct was ethanedial, mono[(4-chlorophenyl)hydrazone], ascharacterized by ¹ H NMR.

EXAMPLE 2

This example illustrates Reaction I, the production of a β-keto ester byreacting a hydrazone aldehyde and diazo ester in the presence of a Lewisacid.

To a slurry of 10.3 g (0.06 mol) of hydrazone aldehyde (ethanedial,mono[(4-chlorophenyl)hydrazone]) in 600 mL of methylene chloride at 25°C., 2.55 g (0.014 mol) of tin(II) chloride was added. Then, 6.78 g (0.06mol) of ethyldiazo acetate was added. The reaction was stirred for 18 hat 25° C. The reaction mixture was diluted with 100 mL of methylenechloride and to the resulting mixture was added 100 mL of water. Afterstirring for 5 minutes, the mixture was filtered through celite and themethylene chloride layer was separated and concentrated under reducedpressure to obtain a dark brown residue. The product, butanoic acid(4-[(4-chlorophenyl)-(1-hydrazinyl-2-ylidene)]-3-oxo-) ethyl ester, waspurified by crystallization from ether and hexane as a yellow solid(8.20 g, 54.2% yield), m.p. 100-100.5° C.

EXAMPLE 3

This example illustrates Reaction II, wherein a β-keto ester is reactedwith an alkyl acid halide to produce a pyridazinone compound having thegeneral Formula I.

A solution of 0.5 g (1.87 mmol) of the β-keto ester produced in Example8 in 10 mL of toluene was treated with 0.21 g (2.79 mmol) of Ca(OH)₂.The slurry was stirred for 2 h at 25° C. Propionyl chloride (0.25 g,2.79 mmol) was then added slowly, and the reaction was stirred for 5h at25° C.

At this time 10 mL of water and 20 mL of 5N HCl was added, and thereaction was stirred for 30 minutes to solubilize the calcium salts.

The top toluene layer was separated (the bottom aqueous layer wasdiscarded) and heated to 80° C. for 2 h. After cooling excess solventwas removed under reduced pressure to yield 0.57 g of an amber solid.This product was 95% pure by ¹ H NMR (99.8% yield). 180 mg of the crudeproduct was purified by chromatography (silica gel, 50% ethyl acetate inhexane) to yield 160 mg of pure product, 4-pyridazinecarboxylic acid(2-(4-chlorophenyl)-3-ethyl-2,5-dihydro-5-oxo-) ethyl ester, as a yellowsolid, m.p. 130-131° C.

EXAMPLE 4

This example illustrates the synthesis of a β-keto ester from hydrazonealdehyde and ethyl diazoacetate, shown in the reaction below: ##STR11##

A dry reactor is charged with 162.2 g of a solution of 10.0 wt-% ethyldiazoacetate in toluene, and 20.0 g of [(4-chlorophenyl)hydrazono]acetaldehyde. The slurry is then cooled to 0° C.

To the cooled slurry is added 8.09 mL of 1.00 M tin (IV) chloridesolution in toluene over a period of 80 min. The temperature of theslurry is maintained below 5° C. during the addition.

The mixture is then allowed to warm to room temperature and is stirredfor an additional 2 hours. The reaction is monitored by HPLC analysis.Chemical yield is about 67.5%. All of the hydrazone aldehyde isconsumed.

EXAMPLE 5

This example illustrates the synthesis of a diketo ester from a β-ketoester, shown in the reaction below: ##STR12##

To the agitated crude reaction mixture at 22° C. from Example 4, isadded 8.45 g of calcium hydroxide. The reactor is then charged with 1.34g of 4-dimethylaminopyridine (DMAP).

Propionyl chloride (9.81 g ) is then added over a period of 10 min. Thetemperature of the mixture increases from 28to 32° C. The reaction iscomplete after the propionyl chloride is added based on HPLC analysis.The chemical yield is about 90%.

EXAMPLE 6

This example illustrates the synthesis of the ethyl ester from thediketo ester of Example 6, shown in the reaction below: ##STR13##

To the vigorously agitated crude reaction mixture from Example 5 isadded 68 mL of 1.2 N HCl (aq.). The biphasic system is heated to 80° C.and this temperature is maintained for 1 hour. The reaction is completebased on HPLC analysis.

The contents are filtered at 80° C. to remove insoluble materials thatare suspended in the aqueous layer. The filtration is complete within 1h. The aqueous layer is separated from the organic layer, and theorganic layer (top) (191 g) contains the ethyl ester, and can then beused to produce the free acid. The aqueous layer (bottom) is discarded.The chemical yield is about 90%.

EXAMPLE 7

This example illustrates the synthesis of the free acid of the ethylester of Example 6 via saponification and acidification, shown in thereaction below: ##STR14##

To the vigorously agitated reaction mixture from Example 7, is added 137g of 15% w/w aqueous sodium hydroxide solution. The biphasic system isheated to 60° C. and is stirred for 2 h. The layers are separated. Thetop organic phase is discarded. The bottom aqueous layer (165 g) istreated with 100 mL isopropanol.

To this mixture is added 50 mL of concentrated hydrochloric acid (37%wt) over 10 min. The resulting mixture is cooled to room temperaturewhile stirring (30 min). The contents are filtered, and the filteredcake is washed with 50 mL of isopropanol. The chemical yield is about95%. After air drying, 13 g of solid with greater than 95% purity of thefree acid was isolated, as characterized by ¹ H and ¹³ C NMR.

EXAMPLE 8

This example illustrates the synthesis of hydrazone aldehyde in acontinuous process, shown in the reaction below: ##STR15##

4-Chlorophenylhydrazine hydrochloride (21.77 g, 0.12 mole) is dissolvedin 600 mL of hot DI water (60° C.). The solution is then filtered toremove the insoluble materials and the solution volume is adjusted to600 mL and maintained at 60° C. Glyoxal (40% by wt., 21.75 g, 0.15moles) is diluted in 600 mL of water and is preheated to 60° C. In theCSTR (Continuous Stirred Tank Reactor) 300 mL of DI water is charged andpreheated to 60° C. The solutions of hydrazine as well as glyoxal arecontinuously added to the stirred reactor (agitation speed, 300 rpm) atthe rate of 24 mL/minute. The reaction temperature (60° C.) in thereactor was maintained by external heating. The overflow wascontinuously filtered using a Buchner funnel. After the completeaddition of glyoxal and hydrazine solution, the reaction mixture wasallowed to stir at 60° C. for another 25 minutes and then filtered. Thewet cake was light yellow in color and filtration was very fast. Thecake was washed twice with DI water (50 mL each) and sucked dry undervacuum. After about 18 h, the moisture content of the wet cake was0.15%. Total mass of the product was 20.0 g (92% yield, assay 99.5%).

All of the compositions and methods disclosed and claimed herein can bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions and methods of this invention havebeen described in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to thecompositions or methods and in the steps or in the sequence of steps ofthe method described herein without departing from the concept, spiritand scope of the invention. More specifically, it will be apparent thatcertain agents which are both chemically and physiologically related maybe substituted for the agents described herein while the same or similarresults would be achieved. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

What is claimed is:
 1. A process for the production of a hydrazoneβ-keto ester of Formula III: ##STR16## wherein R₁ is an alkyl,cycloalkyl, aryl or heteroaromatic group; and R₂ is an alkyl group;comprising contacting a diazo ester of the formula ##STR17## with ahydrazone aldehyde of the formula ##STR18## in the presence of a Lewisacid.
 2. The process of claim 1 wherein the diazo ester is an alkyl orbenzyl diazo acetate.
 3. The process of claim 2 wherein the diazo esteris ethyl diazo acetate.
 4. The process of claim 2 wherein the diazoester is isopropyl diazo acetate.
 5. The process of claim 1 wherein theLewis acid is a tin(II) or tin(IV) compound.
 6. The process of claim 5wherein the Lewis acid is SnCl₂ or SnCl₄.
 7. The process of claim 1wherein the contacting is conducted in the presence of an organicsolvent.
 8. The process of claim 7 wherein the solvent is toluene,cumene, benzene, ethylbenzene, diethyl ether, dibutyl ether, butyl ethylether, chlorobenzene, nitrobenzene, ortho-dichlorobenzene, methylenechloride or dichloroethane.
 9. The process of claim 1 wherein thecontacting is conducted at a temperature between about 0° C. and 25° C.10. The process of claim 1 wherein the hydrazone aldehyde and diazoester are added in a ratio of between about 1:2 and about 2:1.
 11. Theprocess of claim 1 wherein the hydrazone aldehyde is ethanedial,mono[(4-chlorophenyl)hydrazone].
 12. A process for the production of apyridazinone compound of formula I: ##STR19## wherein R₁ is an alkyl,cycloalkyl, aryl or heteroaromatic group; R₂ is an alkyl group; and R₃is an alkyl or phenyl group; comprising:contacting a diazo ester of theformula ##STR20## with a hydrazone aldehyde of the formula ##STR21## inthe presence of a Lewis acid to produce a hydrazone β-keto ester ofFormula III, ##STR22## contacting the hydrazone β-keto ester with analkyl acid halide in the presence of a base to form a diketo ester, andcontacting the diketo ester with an acid.
 13. The process of claim 12wherein the hydrazone aldehyde is ethanedial,mono[(4-chlorophenyl)hydrazone].
 14. The process of claim 12 wherein theLewis acid is a tin(II) or tin(IV) compound.
 15. The process of claim 14wherein the Lewis acid is SnCl₂ or SnCl₄.
 16. The process of claim 12wherein the diazo ester is an alkyl or benzyl diazo acetate.
 17. Theprocess of claim 16 wherein the diazo ester is ethyl diazo acetate. 18.The process of claim 16 wherein the diazo ester is isopropyl diazoacetate.
 19. The process of claim 12 wherein R₁ is an aryl group. 20.The process of claim 19 wherein the aryl group is a phenyl substitutedwith one or more lower alkyl groups and/or halogen atoms and/or loweralkoxy group.
 21. The process of claim 12 wherein R₁ is a heteroaromaticgroup.
 22. The process of claim 21 wherein the heteroaromatic group isselected from the group consisting of furanyl, thienyl and pyridyl. 23.The process of claim 21 wherein the heteroaromatic group is substitutedwith one or more lower alkyl groups and/or halogen atoms and/or loweralkoxy group.